Molecule Info

Topiramate may cause eye problems. Serious eye problems include: sudden decrease in vision with or without eye pain and redness; blockage of fluid in the eye causing increased pressure in the eye (secondary angle closure glaucoma). These eye problems can lead to permanent loss of vision if not treated. You should call your healthcare professional right away if you have any new eye symptoms.

Topiramate may cause decreased sweating and increased body temperature (fever). People, especially children, should be watched for signs of decreased sweating and fever, especially in hot temperatures. Some people may need to be hospitalized for this condition. Call your healthcare provider right away if you have a high fever, a fever that does not go away, or decreased sweating.

Topiramate can increase the level of acid in your blood (metabolic acidosis). If left untreated, metabolic acidosis can cause brittle or soft bones (osteoporosis, osteomalacia, osteopenia), kidney stones, can slow the rate of growth in children, and may possibly harm your baby if you are pregnant. Metabolic acidosis can happen with or without symptoms. Sometimes people with metabolic acidosis will: feel tired, not feel hungry (loss of appetite), feel changes in heartbeat, or have trouble thinking clearly. Your healthcare provider should do a blood test to measure the level of acid in your blood before and during your treatment with Topiramate. If you are pregnant, you should talk to your healthcare provider about whether you have metabolic acidosis.

Like other antiepileptic drugs, Topiramate may cause suicidal thoughts or actions in a very small number of people, about 1 in 500. Pay attention to any changes and call your doctor right away if you have any of these symptoms, especially if they are new, worse, or worry you: thoughts about suicide or dying, attempts to commit suicide, new or worse depression, new or worse anxiety, feeling agitated or restless, panic attacks, trouble sleeping (insomnia), new or worse irritability, acting aggressive, being angry or violent, acting on dangerous impulses, an extreme increase in activity and talking (mania), or other unusual changes in behavior or mood.

Topiramate may affect how you think, and cause confusion, problems with concentration, attention, memory, or speech, depression or mood problems, tiredness, and sleepiness. Do not stop taking Topiramate without first talking to your doctor. Stopping Topiramate suddenly can cause serious problems.

If you take Topiramate during pregnancy, your baby has a higher risk for birth defects called cleft lip and cleft palate. These defects can begin early in pregnancy, even before you know you are pregnant. There may be other medicines to treat your condition that have a lower chance of birth defects. All women of childbearing age should talk to their healthcare providers about using other possible treatments instead of Topiramate. If the decision is made to use Topiramate, you should use effective birth control (contraception) unless you are planning to become pregnant. Tell your healthcare provider right away if you become pregnant while taking Topiramate. You and your healthcare provider should decide if you will continue to take Topiramatewhile you are pregnant. Metabolic acidosis may have harmful effects on your baby. Talk to your healthcare provider if Topiramate has caused metabolic acidosis during your pregnancy. If you become pregnant while taking Topiramate, talk to your healthcare provider about registering with the North American Antiepileptic Drug Pregnancy Registry. You can enroll in this registry by calling 1-888-233-2334. The purpose of this registry is to collect information about the safety of antiepileptic drugs during pregnancy.

Topiramate may cause high blood ammonia levels. High ammonia in the blood can affect your mental activities, slow your alertness, make you feel tired, or cause vomiting.Taking Topiramate when you are also taking valproic acid can cause a drop in body temperature (hypothermia) to less than 95°F, feeling tired, confusion, or coma.

Monotherapy for adults and children with partial onset seizures and generalized seizures, including tonic-clonic seizures.Adjunctive therapy for adults and children with partial onset seizures or generalized tonic-clonic seizures and seizures associated with Lennox-Gastaut syndrome.Prophylaxis of migraine headache in adults. The usefulness of Topiramate in the acute treatment of migraine headache has not been studied.

Dosage & Administration

General: For optimal seizure control in both adults and children, it is recommended that therapy be initiated at a low dose followed by titration to an effective dose.Adjunctive Therapy: Epilepsy:Adults: Therapy should begin at 25-50 mg nightly for 1 week. Subsequently, at weekly or bi-weekly intervals, the dose should be increased by 25-50 mg/day and taken in 2 divided doses. Dose titration should be guided by clinical outcome. Some patients may achieve efficacy with once-a-day dosing.In clinical trials as adjunctive therapy, 200 mg was effective and was the lowest dosage studied. This is, therefore, considered the minimum effective dose. The usual daily dose is 200-400 mg in 2 divided doses. Individual patients have received doses as high as 1600 mg/day.Since Topiramate is removed from plasma by hemodialysis, a supplemental dose of Topiramate equal to approximately ½ the daily dose should be administered on hemodialysis days. The supplemental dose should be administered in divided doses at the beginning and completion of the hemodialysis procedure. The supplemental dose may differ based on the characteristics of the dialysis equipment being used.These dosing recommendations apply to all adults, including the elderly, in the absence of underlying renal disease. (See Precautions.)Children ≥2 years: The recommended total daily dose of Topiramate as adjunctive therapy is approximately 5-9 mg/kg/day in 2 divided doses. Titration should begin at 25 mg (or less, based on a range of 1-3 mg/kg/day) nightly for the 1st week. The dosage should then be increased at 1- or 2-week intervals by increments of 1-3 mg/kg/day (administered in 2 divided doses), to achieve optimal clinical response. Dose titration should be guided by clinical outcome.Daily doses up to 30 mg/kg/day have been studied and were generally well tolerated.Monotherapy: Epilepsy: General: When concomitant AEDs are withdrawn to achieve monotherapy with topiramate, consideration should be given to the effects this may have on seizure control. Unless safety concerns require an abrupt withdrawal of the concomitant AED, a gradual discontinuation at the rate of approximately 1/3 of the concomitant AED dose every 2 weeks is recommended.When enzyme-inducing drugs are withdrawn, topiramate levels will increase. A decrease in Topiramate dosage may be required if clinically indicated.Adults: Titration should begin at 25 mg nightly for 1 week. The dosage should then be increased at 1 or 2-week intervals by increments of 25 or 50 mg/day, administered in 2 divided doses. If the patient is unable to tolerate the titration regimen, smaller increments or longer intervals between increments can be used. Dose and titration rate should be guided by clinical outcome.The recommended initial target dose for topiramate monotherapy in adults is 100 mg/day and the maximum recommended daily dose is 500 mg. Some patients with refractory forms of epilepsy have tolerated topiramate monotherapy at doses of 1000 mg/day. These dosing recommendations apply to all adults including the elderly in the absence of underlying renal disease.Children: Treatment of children ≥2 years should begin at 0.5-1 mg/kg nightly for the 1st week. The dosage should then be increased at 1- or 2-week intervals by increments of 0.5-1 mg/kg/day, administered in 2 divided doses. If the child is unable to tolerate the titration regimen, smaller increments or longer intervals between dose increments can be used. Dose and dose titration rate should be guided by clinical outcome.The recommended initial target dose range for topiramate monotherapy in children ≥2 years is 3-6 mg/kg/day. Children with recently diagnosed partial onset seizures have received doses of up to 500 mg/day.Migraine: Titration should begin at 25 mg nightly for 1 week. The dosage should then be increased in increments of 25 mg/day administered at 1-week intervals. If the patient is unable to tolerate the titration regimen, longer intervals between dose adjustments can be used.Prophylaxis of Migraine Headache: The recommended total daily dose is 100 mg/day administered in 2 divided doses. Some patients may experience a benefit at a total daily dose of 50 mg/day. Patients have received a total daily dose up to 200 mg/day. Dose and titration rate should be guided by clinical outcome.Administration: Topiramate is available in tablets and a capsule sprinkle formulation. It is recommended that tablets not be broken. The sprinkle formulation is provided for those patients who cannot swallow tablets eg, pediatric and the elderly.Topiramate sprinkle capsules may be swallowed whole or may be administered by carefully opening the capsule and sprinkling the entire contents on a small amount (tsp) of soft food. This drug/food mixture should be swallowed immediately and not chewed. It should not be stored for future use.

Overdosage

Symptoms: Overdoses of topiramate have been reported. Signs and symptoms included: Convulsions, speech disturbances, blurred vision, diplopia, impaired mentation, lethargy, abnormal coordination, stupor, hypotension, abdominal pain, agitation, dizziness, drowsiness and depression. The clinical consequences were not severe in most cases, but deaths have been reported after polydrug overdoses involving topiramate.Topiramate overdose has resulted in severe metabolic acidosis (See Precautions).A patient who ingested a dose calculated to be between 96 and 110 g topiramate was admitted to hospital with coma lasting 20-24 hrs followed by full recovery after 3-4 days.Treatment: In acute topiramate overdose, if the ingestion is recent, the stomach should be emptied immediately by lavage or by induction of emesis. Activated charcoal has been shown to adsorb topiramate in vitro. Treatment should be appropriately supportive. Hemodialysis has been shown to be an effective means of removing topiramate from the body. The patient should be well hydrated.

Contraindications

Hypersensitivity to any component of Topiramate.

Special Precautions

In patients with or without a history of seizures or epilepsy, antiepileptic drugs including Topiramate, should be gradually withdrawn to minimize the potential for seizures or increased seizure frequency. In clinical trials, daily dosages were decreased in weekly intervals by 50-100 mg in adults with epilepsy and by 25-50 mg in adults receiving Topiramate at doses up to 100 mg/day for migraine prophylaxis. In clinical trials of children, Topiramate was gradually withdrawn over a 2- to 8-week period. In situations where rapid withdrawal of Topiramate is medically required, appropriate monitoring is recommended.The major route of elimination of unchanged topiramate and its metabolites is via the kidney. Renal elimination is dependent on renal function and is independent of age. Patients with moderate or severe renal impairment may take 10-15 days to reach steady-state plasma concentrations as compared to 4-8 days in patients with normal renal function.As with all patients, the titration schedule should be guided by clinical outcome (ie, seizure control, avoidance of side effects) with the knowledge that subjects with known renal impairment may require a longer time to reach steady-state at each dose.Adequate hydration while using topiramate is very important. Hydration can reduce the risk of nephrolithiasis (see as follows). Proper hydration prior to and during activities eg, exercise or exposure to warm temperature may reduce the risk of heat-related adverse events (see Adverse Reactions).Mood Disturbances/Depression: An increased incidence of mood disturbances and depression has been observed during topiramate treatment.Suicide Attempt: In the double-blind phases of clinical trials with topiramate in approved and investigational indications, suicide attempts occurred at a rate of 0.003 (13 events/3999 patient years) on topiramate versus 0 (0 event/1430 patient years) on placebo. One completed suicide was reported in a bipolar disorder trial in a patient on topiramate.Nephrolithiasis: Some patients, especially those with a predisposition to nephrolithiasis, may be at increased risk for renal stone formation and associated signs and symptoms eg, renal colic, renal pain or flank pain.Risk factors for nephrolithiasis include prior stone formation, a family history of nephrolithiasis and hypercalciuria. None of these risk factors can reliably predict stone formation during topiramate treatment. In addition, patients taking other medication associated with nephrolithiasis may be at increased risk.Decreased Hepatic Function: In hepatically-impaired patients, topiramate should be administered with caution as the clearance of topiramate may be decreased.Acute Myopia and Secondary Angle Closure Glaucoma: A syndrome consisting of acute myopia associated with secondary angle closure glaucoma has been reported in patients receiving Topiramate. Symptoms include acute onset of decreased visual acuity and/or ocular pain. Ophthalmologic findings can include myopia, anterior chamber shallowing, ocular hyperemia (redness) and increased intraocular pressure. Mydriasis may or may not be present. This syndrome may be associated with supraciliary effusion resulting in anterior displacement of the lens and iris, with secondary angle closure glaucoma. Symptoms typically occur within 1 month of initiating Topiramate therapy. In contrast to primary narrow angle glaucoma, which is rare <40 years, secondary angle closure glaucoma associated with topiramate has been reported in pediatric patients as well as adults. Treatment includes discontinuation of Topiramate, as rapidly as possible in the judgment of the treating physician and appropriate measures to reduce intraocular pressure. These measures generally result in a decrease in intraocular pressure.Oligohydrosis and Hyperthermia: Oligohydrosis (decreased sweating), infrequently resulting in hospitalization, has been reported in association with Topiramate use. Decreased sweating and an elevation in body temperature above normal characterized these cases. Some of these cases were reported after exposure to elevated environmental temperature. The majority of the reports have been in children. Patients, especially pediatric patients treated with Topiramate should be monitored closely for evidence of decreased sweating and increased body temperature, especially in hot weather. Caution should be used when Topiramate is prescribed with other drugs that predispose patients to heat-related disorders; these drugs include, but are not limited to, other carbonic anhydrase inhibitors and drugs with anticholinergic activity.Metabolic Acidosis: Hyperchloremic, non-anion gap, metabolic acidosis (ie, decreased serum bicarbonate below the normal reference range in the absence of respiratory alkalosis) is associated with topiramate treatment. This decrease in serum bicarbonate is due to the inhibitory effect of topiramate on renal carbonic anhydrase. Generally, the decrease in bicarbonate occurs early in the treatment although it can occur at any time during treatment. These decreases are usually mild to moderate (average decrease of 4 mmol/L at doses of ≥100 mg/day in adults and at approximately 6 mg/kg/day in pediatric patients. Rarely, patients have experienced decreases to values <10 mmol/L. Conditions or therapies that predispose to acidosis (eg, renal diseases, severe respiratory disorders, status epilepticus, diarrhea, surgery, ketogenic, diet or certain drugs) may be additive to the bicarbonate lowering effects of topiramate.Chronic metabolic acidosis in pediatric patients can reduce growth rate. The effect of topiramate on growth and bone-related sequelae has not been systematically investigated in the pediatric or adult populations.Depending on underlying conditions, appropriate evaluation including serum bicarbonate levels is recommended with topiramate therapy. If metabolic acidosis develops and persists, consideration should be given to reducing the dose or discontinuing topiramate (use dose tapering).Nutritional Supplementation: A dietary supplement or increased food intake may be considered if the patient is losing weight while on this medication.Effects on the Ability to Drive or Operate Machinery: As with all antiepileptic drugs, Topiramate acts on the CNS and may produce drowsiness, dizziness or other related symptoms. It may cause visual disturbances and/or blurred vision. These adverse events could potentially be dangerous in patients driving a vehicle or operating machinery, particularly until such time as the individual patient's experience with Topiramate is established.

Use in pregnancy & lactation: As with other antiepileptic drugs, topiramate was teratogenic in mice, rats and rabbits. In rats, topiramate crosses the placental barrier.There are no studies using Topiramate in pregnant women. However, Topiramate should be used during pregnancy only if the potential benefit outweighs the potential risk.Topiramate is excreted in the milk of lactating rats. The excretion of topiramate in human milk has not been evaluated in controlled studies. Limited observations in patients suggests an extensive excretion of topiramate into breast milk. Since many drugs are excreted in human milk, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.In post-marketing experience, cases of hypospadias have been reported in male infants exposed in utero to topiramate, with or without other anticonvulsants; however, a causal relationship with topiramate has not been established.

Use in children: Safety and effectiveness in patients <2 years have not been established. Topiramate is associated with metabolic acidosis. Chronic untreated metabolic acidosis in pediatric patients may cause osteomalacia (rickets) and may reduce growth rates. A reduction in growth rate may eventually decrease the maximal height achieved. The effect of topiramate on growth and bone-related sequelae has not been systematically investigated.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The following adverse reactions are discussed in more detail in other sections of the labeling: ï‚· Acute Myopia and Secondary Angle Closureï‚· Oligohidrosis and Hyperthermiaï‚· Metabolic Acidosisï‚· Suicidal Behavior and Ideationï‚· Cognitive/Neuropsychiatric Adverse Reactionsï‚· Fetal Toxicityï‚· Withdrawal of Antiepileptic Drugs (AEDs)ï‚· Sudden Unexplained Death in Epilepsy (SUDEP)ï‚· Hyperammonemia and Encephalopathy (Without and With Concomitant Valproic Acid [VPA] Useï‚· Kidney Stonesï‚· Hypothermia with Concomitant Valproic Acid (VPA) Useï‚· ParesthesiaThe data described in the following sections were obtained using Topiramate (TOPAMAX®) tablet.

Monotherapy Epilepsy Adults ≥16 Years The adverse reactions in the controlled trial that occurred most commonly in adults in the 400 mg/day Topiramate group and at a rate higher (> 5 %) than in the 50 mg/day group were: paresthesia, weight decrease, anorexia, somnolence, and difficulty with memory. Approximately 21% of the 159 adult patients in the 400 mg/day group who received topiramate as monotherapy in the controlled clinical trial discontinued therapy due to adverse reactions. The most common (> 2% more frequent than low-dose 50 mg/day Topiramate) adverse reactions causing discontinuation in this trial were difficulty with memory, fatigue, asthenia, insomnia, somnolence, and paresthesia.

Pediatric Patients 6 to <16 Years of Age The adverse reactions in the controlled trial that occurred most commonly in pediatric patients in the 400 mg/day Topiramate group and at a rate higher (> 5%) than in the 50 mg/day group were fever, weight decrease, mood problems, cognitive problems, infection, flushing, and paresthesia. Approximately 14% of the 77 pediatric patients in the 400 mg/day group who received Topiramate as monotherapy in the controlled clinical trial discontinued therapy due to adverse reactions. The most common (> 2% more frequent than low-dose 50 mg/day Topiramate) adverse reactions resulting in discontinuation in this trial were difficulty with concentration/attention, fever, flushing, and confusion.

Adjunctive Therapy Epilepsy The most commonly observed adverse reactions associated with the use of Topiramate at dosages of 200 to 400 mg/day in controlled trials in adults with partial onset seizures, primary generalized tonic-clonic seizures, or Lennox-Gastaut syndrome, that were seen at greater frequency in Topiramate-treated patients and did not appear to be dose-related were somnolence, dizziness, ataxia, speech disorders and related speech problems, psychomotor slowing, abnormal vision, difficulty with memory, paresthesia and diplopia. The most common dose-related adverse reactions at dosages of 200 to 1,000 mg/day were fatigue, nervousness, difficulty with concentration or attention, confusion, depression, anorexia, language problems, anxiety, mood problems, and weight decrease. Adverse reactions associated with the use of Topiramate at dosages of 5 to 9 mg/kg/day in controlled trials in pediatric patients with partial onset seizures, primary generalized tonic-clonic seizures, or Lennox-Gastaut syndrome, that were seen at greater frequency in Topiramate treated patients were fatigue, somnolence, anorexia, nervousness, difficulty with concentration/attention, difficulty with memory, aggressive reaction, and weight decrease In controlled clinical trials in adults, 11% of patients receiving Topiramate200 to 400 mg/day as adjunctive therapy discontinued due to adverse reactions. This rate appeared to increase at dosages above 400 mg/day. Adverse reactions associated with discontinuing therapy included somnolence, dizziness, anxiety, difficulty with concentration or attention, fatigue, and paresthesia and increased at dosages above 400 mg/day. None of the pediatric patients who received Topiramate adjunctive therapy at 5 to 9 mg/kg/day in controlled clinical trials discontinued due to adverse reactions. Approximately 28% of the 1757 adults with epilepsy who received Topiramateat dosages of 200 to 1,600 mg/day in clinical studies discontinued treatment because of adverse reactions; an individual patient could have reported more than one adverse reaction. These adverse reactions were psychomotor slowing (4.0%), difficulty with memory (3.2%), fatigue (3.2%), confusion (3.1%), somnolence (3.2%), difficulty with concentration/attention (2.9%), anorexia (2.7%), depression (2.6%), dizziness (2.5%), weight decrease (2.5%), nervousness (2.3%), ataxia (2.1%), and paresthesia (2.0%). Approximately 11% of the 310 pediatric patients who received Topiramate at dosages up to 30 mg/kg/day discontinued due to adverse reactions. Adverse reactions associated with discontinuing therapy included aggravated convulsions (2.3%), difficulty with concentration/attention (1.6%), language problems (1.3%), personality disorder (1.3%), and somnolence (1.3%).

In vitro studies indicate that topiramate does not inhibit enzyme activity for CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2D6, CYP2E1, and CYP3A4/5 isozymes. In vitro studies indicate that topiramate is a mild inhibitor of CYP2C19 and a mild inducer of CYP3A4. Drug interactions with some antiepileptic drugs, CNS depressants and oral contraceptives are described here. For other drug interactions, please refer to Clinical Pharmacology.

Antiepileptic Drugs Potential interactions between topiramate and standard AEDs were assessed in controlled clinical pharmacokinetic studies in patients with epilepsy. Concomitant administration of phenytoin or carbamazepine with topiramate decreased plasma concentrations of topiramate by 48% and 40%, respectively when compared to Topiramate given alone [see Clinical Pharmacology (12.3).] Concomitant administration of valproic acid and Topiramate has been associated with hyperammonemia with and without encephalopathy. Concomitant administration of Topiramate with valproic acid has also been associated with hypothermia (with and without hyperammonemia) in patients who have tolerated either drug alone. It may be prudent to examine blood ammonia levels in patients in whom the onset of hypothermia has been reported.

CNS Depressants Concomitant administration of Topiramate and alcohol or other CNS depressant drugs has not been evaluated in clinical studies. Because of the potential of topiramate to cause CNS depression, as well as other cognitive and/or neuropsychiatric adverse reactions, Topiramate should be used with extreme caution if used in combination with alcohol and other CNS depressants.

Oral Contraceptives Exposure to ethinyl estradiol was statistically significantly decreased at doses of 200, 400, and 800 mg/day (18%, 21%, and 30%, respectively) when Topiramate was given as adjunctive therapy in patients taking valproic acid. However, norethindrone exposure was not significantly affected. In another pharmacokinetic interaction study in healthy volunteers with a concomitantly administered combination oral contraceptive product containing 1 mg norethindrone (NET) plus 35 mcg ethinyl estradiol (EE), Topiramate, ï€ given in the absence of other medications at doses of 50 to 200 mg/day, was not associated with statistically significant changes in mean exposure (AUC) to either component of the oral contraceptive. The possibility of decreased contraceptive efficacy and increased breakthrough bleeding should be considered in patients taking combination oral contraceptive products with Topiramate. Patients taking estrogen-containing contraceptives should be asked to report any change in their bleeding patterns. Contraceptive efficacy can be decreased even in the absence of breakthrough bleeding.

Metformin Topiramate treatment can frequently cause metabolic acidosis, a condition for which the use of metformin is contraindicated.

Lithium In patients, lithium levels were unaffected during treatment with topiramate at doses of 200 mg/day; however, there was an observed increase in systemic exposure of lithium (27% for Cmax and 26% for AUC) following topiramate doses of up to 600 mg/day. Lithium levels should be monitored when co-administered with high-dose Topiramate.

Other Carbonic Anhydrase Inhibitors Concomitant use of topiramate, a carbonic anhydrase inhibitor, with any other carbonic anhydrase inhibitor (e.g., zonisamide, acetazolamide, or dichlorphenamide) may increase the severity of metabolic acidosis and may also increase the risk of kidney stone formation. Therefore, if Topiramate is given concomitantly with another carbonic anhydrase inhibitor, the patient should be monitored for the appearance or worsening of metabolic acidosis.

Topiramate (topiramate) can cause fetal harm when administered to a pregnant woman. Data from pregnancy registries indicate that infants exposed to topiramate in utero have an increased risk for cleft lip and/or cleft palate (oral clefts). When multiple species of pregnant animals received topiramate at clinically relevant doses, structural malformations, including craniofacial defects, and reduced fetal weights occurred in offspring. Topiramate should be used during pregnancy only if the potential benefit outweighs the potential risk. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus [see Use in Specific Populations (8.9)]. Pregnancy Registry Patients should be encouraged to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry if they become pregnant. This registry is collecting information about the safety of antiepileptic drugs during pregnancy. Human Data Data from the NAAED Pregnancy Registry indicate an increased risk of oral clefts in infants exposed to topiramate monotherapy during the first trimester of pregnancy. The prevalence of oral clefts was 1.2% compared to a prevalence of 0.39% - 0.46% in infants exposed to other AEDs, and a prevalence of 0.12% in infants of mothers without epilepsy or treatment with other AEDs. For comparison, the Centers for Disease Control and Prevention (CDC) reviewed available data on oral clefts in the United States and found a similar background rate of 0.17%. The relative risk of oral clefts in topiramate-exposed pregnancies in the NAAED Pregnancy Registry was 9.6 (95% Confidence Interval = CI 3.6 â€“ 25.7) as compared to the risk in a background population of untreated women. The UK Epilepsy and Pregnancy Register reported a similarly increased prevalence of oral clefts of 3.2% among infants exposed to topiramate monotherapy. The observed rate of oral clefts was 16 times higher than the background rate in the UK, which is approximately 0.2%. Topiramate treatment can cause metabolic acidosis [see Warnings and Precautions (5.3)]. The effect of topiramate-induced metabolic acidosis has not been studied in pregnancy; however, metabolic acidosis in pregnancy (due to other causes) can cause decreased fetal growth, decreased fetal oxygenation, and fetal death, and may affect the fetusâ€™ ability to tolerate labor. Pregnant patients should be monitored for metabolic acidosis and treated as in the nonpregnant state [see Warnings and Precautions (5.3)]. Newborns of mothers treated with Topiramate should be monitored for metabolic acidosis because of transfer of topiramate to the fetus and possible occurrence of transient metabolic acidosis following birth.

Animal Data

Topiramate has demonstrated selective developmental toxicity, including teratogenicity, in multiple animal species at clinically relevant doses. When oral doses of 20, 100, or 500 mg/kg were administered to pregnant mice during the period of organogenesis, the incidence of fetal malformations (primarily craniofacial defects) was increased at all doses. The low dose is approximately 0.2 times the recommended human dose (RHD) 400 mg/day on a mg/m2 basis. Fetal body weights and skeletal ossification were reduced at 500 mg/kg in conjunction with decreased maternal body weight gain. In rat studies (oral doses of 20, 100, and 500 mg/kg or 0.2, 2.5, 30, and 400 mg/kg), the frequency of limb malformations (ectrodactyly, micromelia, and amelia) was increased among the offspring of dams treated with 400 mg/kg (10 times the RHD on a mg/m2 basis) or greater during the organogenesis period of pregnancy. Embryotoxicity (reduced fetal body weights, increased incidence of structural variations) was observed at doses as low as 20 mg/kg (0.5 times the RHD on a mg/m2 basis). Clinical signs of maternal toxicity were seen at 400 mg/kg and above, and maternal body weight gain was reduced during treatment with 100 mg/kg or greater.

Labor and Delivery Although the effect of Topiramate on labor and delivery in humans has not been established, the development of topiramate-induced metabolic acidosis in the mother and/or in the fetus might affect the fetusâ€™ ability to tolerate labor.

Nursing Mothers Limited data on 5 breastfeeding infants exposed to topiramate showed infant plasma topiramate levels equal to 10-20% of the maternal plasma level. The effects of this exposure on infants are unknown. Caution should be exercised when administered to a nursing woman. Pediatric Use Adjunctive Treatment for Partial Onset Epilepsy in Infants and Toddlers (1 to 24 months) Safety and effectiveness in patients below the age of 2 years have not been established for the adjunctive therapy treatment of partial onset seizures, primary generalized tonic-clonic seizures, or seizures associated with Lennox-Gastaut syndrome. In a single randomized, double-blind, placebo-controlled investigational trial, the efficacy, safety, and tolerability of topiramate oral liquid and sprinkle formulations as an adjunct to concurrent antiepileptic drug therapy in infants 1 to 24 months of age with refractory partial onset seizures were assessed. After 20 days of double-blind treatment, topiramate (at fixed doses of 5, 15, and 25 mg/kg/day) did not demonstrate efficacy compared with placebo in controlling seizures. In general, the adverse reaction profile in this population was similar to that of older pediatric patients, although results from the above controlled study and an open-label, long-term extension study in these infants/toddlers (1 to 24 months old) suggested some adverse reactions/toxicities (not previously observed in older pediatric patients and adults; i.e., growth/length retardation, certain clinical laboratory abnormalities, and other adverse reactions/toxicities that occurred with a greater frequency and/or greater severity than had been recognized previously from studies in older pediatric patients or adults for various indications. These very young pediatric patients appeared to experience an increased risk for infections (any topiramate dose 12%, placebo 0%) and of respiratory disorders (any topiramate dose 40%, placebo 16%). The following adverse reactions were observed in at least 3% of patients on topiramate and were 3% to 7% more frequent than in patients on placebo: viral infection, bronchitis, pharyngitis, rhinitis, otitis media, upper respiratory infection, cough, and bronchospasm. A generally similar profile was observed in older children.

Geriatric Use In clinical trials, 3% of patients were over 60. No age-related differences in effectiveness or adverse effects were evident. However, clinical studies of topiramate did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently than younger subjects. Dosage adjustment may be necessary for elderly with impaired renal function (creatinine clearance rate <70 mL/min/1.73 m2) due to reduced clearance of topiramate.

Race and Gender Effects Evaluation of effectiveness and safety in clinical trials has shown no race- or gender-related effects.

Pharmacology: Pharmacodynamics: Topiramate is a novel antiepileptic agent classified as a sulfamate-substituted monosaccharide. The precise mechanism by which topiramate exerts its antiseizure effect is unknown. Electrophysiological and biochemical studies on cultured neurons have identified 3 properties that may contribute to the antiepileptic efficacy of topiramate.Action potentials elicited repetitively by a sustained depolarization of the neurons were blocked by topiramate in a time-dependent manner, suggestive of a state-dependent sodium-channel blocking action. Topiramate increased the frequency at which gamma-aminobutyrate (GABA) activated GABAA receptors and enhanced the ability of GABA to induce a flux of chloride ions into neurons, suggesting that topiramate potentiates the activity of this inhibitory neurotransmitter.This effect was not blocked by flumazenil, a benzodiazepine antagonist, nor did topiramate increase the duration of the channel open time, differentiating topiramate from barbiturates that modulate GABAA receptors.Because the antiepileptic profile of topiramate differs markedly from that of the benzodiazepines, it may modulate a benzodiazepine-insensitive subtype of GABAA receptor. Topiramate antagonized the ability of kainate to activate the kainate/AMPA (Î±-amino-3-hydroxy-5-methylisoxazole-4-propionic acid) subtype of excitatory amino acid (glutamate) receptor, but had no apparent effect on the activity of N-methyl-D-aspartate (NMDA) at the NMDA receptor subtype. These effects of topiramate were concentration-dependent over a range of 1-200 mcM, with minimum activity observed at 1-10 mcM.In addition, topiramate inhibits some isoenzymes of carbonic anhydrase. This pharmacologic effect is much weaker than that of acetazolamide, a known carbonic anhydrase inhibitor and is not thought to be a major component of topiramate's antiepileptic activity.In animal studies, topiramate exhibits anticonvulsant activity in rat and mouse maximal electroshock seizure (MES) tests and is effective in rodent models of epilepsy, which include tonic and absence-like seizures in the spontaneous epileptic rat (SER) and tonic and clonic seizures induced in rats by kindling of the amygdala or by global ischemia. Topiramate is only weakly effective in blocking clonic seizures induced by the GABAA receptor antagonist, pentylenetetrazole.Studies in mice receiving concomitant administration of topiramate and carbamazepine or phenobarbital showed synergistic anticonvulsant activity, while combination with phenytoin showed additive anticonvulsant activity. In well-controlled add-on trials, no correlation has been demonstrated between trough plasma concentrations of topiramate and its clinical efficacy. No evidence of tolerance has been demonstrated in man.Pharmacokinetics: The tablet and sprinkle formulations are bioequivalent.The pharmacokinetic profile of topiramate compared to other antiepileptic drugs shows a long plasma t½, linear pharmacokinetics, predominantly renal clearance, absence of significant protein-binding and lack of clinically relevant active metabolites.Topiramate is not a potent inducers of drug metabolizing enzymes, can be administered without regard to meals and routine monitoring of plasma topiramate concentrations is not necessary. In clinical studies, there was no consistent relationship between plasma concentrations and efficacy or adverse events.Topiramate is rapidly and well absorbed. Following oral administration of 100 mg topiramate to healthy subjects, a mean peak plasma concentration (Cmax) of 1.5 mcg/mL was achieved within 2-3 hrs (Tmax). Based on the recovery of radioactivity from the urine, the mean extent of absorption of a 100-mg oral dose of 14C-topiramate was at least 81%. There was no clinically significant effect of food on the bioavailability of topiramate. Generally, 13-17% of topiramate is bound to plasma protein. A low capacity binding site for topiramate in/on erythrocytes that is saturable above plasma concentrations of 4 mcg/mL has been observed. The volume of distribution varied inversely with the dose. The mean apparent volume of distribution was 0.8-0.55 L/kg for a single dose range of 100-1200 mg. An effect of gender on the volume of distribution was detected, with values for females circa 50% of those for males. This was attributed to the higher percent body fat in female patients and is of no clinical consequence.Topiramate is not extensively metabolized (~20%) in healthy volunteers. It is metabolized up to 50% in patients receiving concomitant antiepileptic therapy with known inducers of drug-metabolizing enzymes. Six metabolites, formed through hydroxylation, hydrolysis and glucuronidation have been isolated, characterized and identified from plasma, urine and feces of humans. Each metabolite represents <3% of the total radioactivity excreted following administration of 14C-topiramate. Two metabolites, which retained most of the structure of topiramate, were tested and found to have little or no anticonvulsant activity.In humans, the major route of elimination of unchanged topiramate and its metabolites is via the kidney (at least 81% of the dose). Approximately 66% of a dose of 14C-topiramate was excreted unchanged in the urine within 4 days. Following twice-a-day dosing with 50 and 100 mg of topiramate, the mean renal clearance was approximately 18 and 17 mL/min, respectively. There is evidence of renal tubular reabsorption of topiramate. This is supported by studies in rats where topiramate was co-administered with probenecid and a significant increase in renal clearance of topiramate was observed. Overall, plasma clearance is approximately 20-30 mL/min in humans following oral administration.Topiramate exhibits low intersubject variability in plasma concentrations and, therefore, has predictable pharmacokinetics. The pharmacokinetics of topiramate are linear with plasma clearance remaining constant and area under the plasma concentration curve increasing in a dose-proportional manner over a 100- to 400-mg single oral dose range in healthy subjects. Patients with normal renal function may take 4-8 days to reach steady-state plasma concentrations. The mean Cmax following multiple, twice-a-day oral doses of 100 mg to healthy subjects was 6.76 mcg/mL. Following administration of multiple doses of 50 and 100 mg of topiramate twice a day, the mean plasma elimination t½ was approximately 21 hrs.Concomitant multiple-dose administration of topiramate 100-400 mg twice a day, with phenytoin or carbamazepine shows dose-proportional increases in plasma concentrations of topiramate.The plasma and renal clearance of topiramate are decreased in patients with impaired renal function (creatinine clearance â‰¤60 mL/min) and the plasma clearance is decreased in patients with end-stage renal disease. As a result, higher steady-state topiramate plasma concentrations are expected for a given dose in renal-impaired patients as compared to those with normal renal function. Topiramate is effectively removed from plasma by hemodialysis.Plasma clearance of topiramate is decreased in patients with moderate to severe hepatic impairment.Plasma clearance of topiramate is unchanged in elderly subjects in the absence of underlying renal disease.Pediatric Pharmacokinetics up to 12 years: The pharmacokinetics of topiramate in children, as in adults receiving add-on therapy, are linear, with clearance independent of dose and steady-state plasma concentrations increasing in proportion to dose. Children, however, have a higher clearance and a shorter elimination t½. Consequently, the plasma concentrations of topiramate for the same mg/kg dose may be lower in children compared to adults. As in adults, hepatic enzyme-inducing antiepileptic drugs decrease the steady-state plasma concentrations.Toxicology: Preclinical Safety Data: Acute and long-term exposure of mice, rats, dogs and rabbits to topiramate was well-tolerated. Hyperplasia of the gastric epithelial cells was observed only in rodents and in rats and was reversible after 9 weeks without treatment.Tumors of smooth muscle origin in the urinary bladder were seen only in mice (oral dosages up to 300 mg/kg for 21 months) and appear to be unique to the species. Since no human counterpart exists, they were not considered clinically relevant. No such findings occurred in the rat carcinogenicity study (oral dosages up to 120 mg/kg/day for 24 months). Other toxicologic and pathologic effects of topiramate observed in these studies may be related to the weak induction of drug-metabolizing enzymes or weak carbonic anhydrase inhibition.Despite maternal and paternal toxicity as low as 8 mg/kg/day, no effects on fertility were observed, in male or female rats with up to 100 mg/kg/day.As with other antiepileptic drugs, topiramate has been shown to have teratogenic effects in mice, rats and rabbits. In mice, fetal weights and skeletal ossification were reduced at 500 mg/kg/day in conjunction with maternal toxicity. Overall numbers of fetal malformations in mice were increased for all drug-treated groups (20, 100 and 500 mg/kg/day), but no significant differences or dosage-response relationships were observed for overall or specific malformations, suggesting that other factors eg, maternal toxicity may be involved.In rats, dosage-related maternal and embryo/fetal toxicity (reduced fetal weights and/or skeletal ossification) were observed down to 20 mg/kg/day with teratogenic effects (limb and digit defects) at ≥400 mg/kg/day. In rabbits, dosage-related maternal toxicity was noted down to 10 mg/kg/day with embryo/fetal toxicity (increased lethality) down to 35 mg/kg/day and teratogenic effects (rib and vertebral malformations) at 120 mg/kg/day.The teratogenic effects seen in rats and rabbits were similar to those seen with carbonic anhydrase inhibitors, which have not been associated with malformations in humans. Effects on growth were also indicated by lower weights at birth and during lactation for pups from female rats treated with 20 or 100 mg/kg/day during gestation and lactation. In rats, topiramate crosses the placental barrier.In juvenile rats, daily oral administration of topiramate at doses up to 300 mg/kg/day during the period of development corresponding to infancy, childhood and adolescence resulted in toxicities similar to those in adult animals (decreased food consumption with decreased body weight gain, centrolobullar hepatocellular hypertrophy and slight urothelial hyperplasia in the urinary bladder). There were no relevant effects on long bone (tibia) growth or bone (femur) mineral density, preweaning and reproductive development, neurological development (including assessments on memory and learning), mating and fertility or hysterotomy parameters.In a battery of in vitro and in vivo mutagenicity assays, topiramate did not show genotoxic potential.